Process for the preparation of travoprost

ABSTRACT

The invention relates to a process for the preparation of travoprost of formula (I), comprising that, the compound of formula (II), is stereo selectively reduced, the resulting compound of formula (III), is if desired crystallized, the lactone group of the compound of formula (III) is reduced, the p-phenyl-benzoyl protecting group of the thus obtained compound of formula (IV), is removed, the resulting triol of formula (V), is, if desired after crystallization, transformed by Wittig reaction into the acid of formula (VI), which is then esterified.

The subject of our invention is a novel process for the preparation oftravoprost. Travoprost of formula (I)

is a known prostaglandin derivative used for the treatment of glaucomaand high eye pressure (U.S. Pat. No. 5,510,383).

Processes for the preparation of travoprost are disclosed for example inEP 2143712, WO 2011/046569, WO 2011/055377.

The process according to EP 2143 712 is shown on FIG. 1.

Stereoselectivity of the enone→enol reduction is 88.7% (Example 10.).

According to the process disclosed in WO 2011/046569 the 15-epi impurityis removed by protection of the OH-groups of the diol withtert-butyl-dimethylsilyl group (TBDMS) and crystallization of the thusobtained protected diol.

In the process according to WO 2011/055377 the enone→enol transformationis carried out with N,N-diethylaniline-borane complex as reducing agent,in the presence of Corey catalyst (CBS-oxazaborolidine). The product ispurified by preparative HPLC.

The overall yield is 7%.

We aimed to work out a process with higher stereoselectivity and betteryield.

The subject of our invention is the preparation of travoprost of formula(I)

bystereoselective reduction of the compound of formula (II),

reduction of the lactone group of the resulting compound of formula(III),

removal of the p-phenylbenzoyl protecting group of the thus obtainedcompound of formula (IV),

transformation of the resulting triol of formula (V) by Wittig reaction

into the acid of formula (V)which is

then esterified.

The starting compound of formula (II) can be prepared for example byoxidation of the PPB-Corey-lactone of formula (XII)

into the

aldehyde, which is then transformed with the phosphonate of formula(XIII)

in HWE reaction, in water free medium, in the presence of solidpotassium hydroxide into the compound of formula (II).

According to one embodiment of the process based on the invention, thePPB-Corey-lactone is oxidized under Pfitzner-Moffatt reaction conditionsinto the aldehyde (Pfitzner, K. E., Moffatt J. G.; J. Am. Chem. Soc.1963, 85, 3027), then the lower chain is built up with the help ofHorner-Wadsworth-Emmons (HWE) reaction (Wadsworth, W.; Org. React.,1977, 25, 73)—by use of the appropriate phosphonate—under water-freeconditions, in the presence of solid potassium hydroxide. For thedeprotonation of the phosphonate—instead of using the widely describedsodium hydride, potassium tert-butylate, lithium carbonate, DBU,lithium- or magnesium halogenides, triethylamine, potassium hexamethyldisilazide (KHMDS) or crown ether bases—we applied solid potassiumhydroxide which is economical and can be safely used in industrialscale.

The HWE reaction is carried out in an aprotic organic solvent in atemperature range of 40-(−50)° C., preferably at (−10)° C., by using assolvent an aromatic hydrocarbon, such as toluene or an ether, liketetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether,dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, diethylether or their mixtures. According to another embodiment of theinvention, the selective reduction of the compound of formula (II) isaccomplished with a borane-type reducing agent.

As the borane-type reducing agent borane-dimethyl sulfide,(−)-B-chlorodiisopinocampheylborane (DIP-Cl), catecholborane, especiallycatecholborane may be applied. According to a further embodiment of theprocess the reduction of the compound of formula (II) is carried out inthe presence of a chiral catalyst. As chiral catalystCBS-oxazaborolidine can be used. The reaction is carried out in thepresence of an organic solvent, at a temperature between (10° C.) and(−80° C.), preferably between (−10° C.) and (−20° C.). As for solventtoluene, hexane, heptane, pentane, tetrahydrofuran,methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane,tert-butyl methyl ether, diisopropyl ether, diethyl ether or theirmixtures may be applied, among others toluene-tetrahydrofuran mixturesare used.

The resulting compound of formula (III) is purified by crystallization,while the amount of the undesired isomer is lowered in a significantmanner. The crystalline form of the compound of formula (III) has notbeen known before, it is a novel form. Crystallization is carried out inpolar or apolar solvents or in the mixture of them.

In an embodiment of the process according to the invention thecrystallization is performed between (−20)-70° C., in such a way thatthe material is dissolved in alcohol at reflux temperature andcrystallized by cooling gradually. The crystals are then filtered off,washed and dried.

Reduction of the compound of formula (III) may be carried out withdiisobutyl-aluminum hydride (DIBAL-H). As for solvent, inert aproticsolvents such as THF, toluene, hexane, and heptane may be applied. Thereaction is performed at a temperature between (−80° C.) and (−50° C.),especially between (−80° C.) and (−70° C.).

The product of the DIBAL-H reduction, the intermediate of formula (IV),is a novel compound.

The PPB-protecting group may be removed in a known way by methanolysis,under basic conditions, especially in the presence of potassiumcarbonate.

In a further embodiment of the process, the resulting intermediate offormula (V) is purified by crystallization, while the amount of theundesired isomer is decreased under a strickt limit value. Thecrystalline form of the compound of formula (V) has not been describedbefore, it is a novel form. Crystallization is carried out in themixture of polar and apolar solvents. As for the mixture of polar andapolar solvents, an ethyl acetate-hexane mixture may be used.Transformation of the compound of formula (V) into the compound offormula (VI) is accomplished by Wittig reaction, while esterification ofthe compound of formula (VI) is carried out with isopropyl iodide.

In the esterification reaction cyclic tertiary amides, such asN-methylpyrrolidone and/or 1,3-dimethylimidazolidinone are used assolvents. The esterification is performed at a temperature between20-90° C., especially between 40-50° C.

A further subject of the invention is the novel compound of formula (IV)

and its use for the preparation of Travoprost.

Furthermore, the subject of the invention is the crystalline compound offormula (III),

having the melting point of 129.5-134.5° C., and its use for thepreparation of Travoprost.

Furthermore, the subject of the invention is the crystalline compound offormula (V),

having the melting point of 85.4-86.6° C., and its use for thepreparation of Travoprost.

One embodiment of the full synthesis of Travoprost according to theinvention is demonstrated on Scheme 1 below:

In one embodiment of the invention, which starts from thePPB-Corey-lactone, the lower chain is constructed with the help of theappropriate phosphonate, by Horner-Wadsworth-Emmons reaction. For thedeprotonation of the phosphonate the inexpensive and in industrial scalesafely applicable solid potassium hydroxide is used. Reduction of theresulting Travoprost 1. intermediate (enone-compound of Formula (II)) iscarried out in the presence of a 2-methyl-CBS-oxazaborolidine catalyst,with a borane-type reducing agent, like catecholborane, resulting in astereoselectivity of 90%. The thus obtained Travoprost 2. intermediate(enol—compound of Formula (III)) is purified by crystallization andreduced with diisobutylaluminum hydride (DIBAL-H). From the resultingTravoprost 3. intermediate (PPB-triol—compound of Formula (IV)) thePPB-protecting group is removed and the thus obtained Travoprost 4.intermediate (triol-compound of Formula (V)) is purified bycrystallization. Travoprost 5. intermediate (acid-compound of FormulaVI) is prepared by Wittig reaction. Finally, the esterification iscarried out with isopropyl iodide in DMI(1,3-dimethylimidazolidin-2-one) solvent to obtain the ester(Travoprost—Formula (I)).

Advantages of the process introduced by the invention:

-   -   In the HWE reaction, to prepare the starting compound of formula        (II), the deprotonation of the phosphonate is carried out with        the inexpensive and in industrial scale safely applicable solid        potassium hydroxide—instead of the expensive and flammable        sodium hydride which is commonly and widely used in the present        practice.    -   The use of CBS-oxazaborolidine and catecholborane for the        reduction of the 15-oxo group in the synthesis of travoprost is        a new solution, not applied before, by which a diastereomeric        excess even higher than 90-92% may be reached. In the method        described in EP 2 143712 the selectivity is de(S)=88.7%, using        DIP-Cl. In the process disclosed in WO 2011/055377 A1, beside        the CBS catalyst N,N-diethylaniline-borane complex is applied,        but the extent of stereoselectivity is not given.    -   The purification strategy is fully novel, since removal of the        15-epi-impurity is accomplished by crystallization, without        chromatography, in a high yield, contrary to the MPLC (medium        pressure chromatography purification method) (WO 2011/046569 A1)        or preparative HPLC (WO 2011/055377 A1) methods known in the        literature.    -   The crystalline form of the compound of formula (III) and that        of the compound of formula (V) have not been described in the        literature before. In the present process the crystalline form        is also utilized for the purification of the intermediates and        removal of the undesired isomer.    -   In the esterification step, as a novel solvent,        1,3-dimethylimidazolidinone (DMI) is used, which is not strongly        toxic, in contrast to the generally used dimethylformamide (EP 2        143 712 A1, WO 2011/046569 A1). DMI is a solvent used in the        beauty industry. As a further advantage, the formyl-impurities        which generate from the widely used dimethylformamide solvent,        are not formed from DMI. The esterification reaction can be        carried out with very high conversion, without forming new        impurities (˜100%).    -   The overall yield of the new process is very high, 16%, which is        more than double of the yield described in WO 2011/055377 A1        (7%).    -   Further details of the invention are included, but not limited        to the examples below.

EXAMPLES 1. Construction of the Lower Chain (Oxidation and HWE Reaction)Preparation of the [1,1′-Biphenyl]-4-carboxylic acid,(3aR,4R,5R,6aS)-hexahydro-2-oxo-4-[(1E)-3-oxo-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]-2H-cyclopenta[b]furan-5-ylester /compound of formula (II)/

1069 g of PPB-Corey-lactone is suspended in an inert atmosphere in 11.1L of water-free toluene. To this suspension are added 1.4 L ofdiisopropylcarbodiimide and then 0.855 L of dimethyl sulfoxide inphosphoric acid. The reaction mixture is heated to 50° C. and a further0.34 L of dimethyl sulfoxide in phosphoric acid is added in portions.After the accomplishment of the oxidation reaction, the mixture iscooled to −10° C. and while that temperature is maintained, 316 g ofpotassium hydroxide followed by 1.45 kg of Travoprost phosphonate intoluene solution are added. When the HWE reaction has completed, thereaction mixture is poured onto 1 M hydrochloric acid solution and themixture is stirred. The precipitated crystals are filtered off andwashed. The phases of the filtrate are separated, the organic phase iswashed with 1M sodium hydrogen carbonate solution and then with dilutedhydrochloric acid solution. The organic phase is evaporated and purifiedby chromatography on a silica gel column (eluent: toluene-ethyl acetatemixture). The main fraction is evaporated and crystallized from ethylacetate-hexane mixture.

Yield: 915 g, 55%.

Melting point: 112.5-114.5° C.

IR spectrum of Travoprost 1. intermediate is shown on FIG. 2.

Travoprost 1. intermediate ¹H, ¹³C and ¹⁹F NMR data:

Travoprost 1. intermediate (enone—Formula (II)):

Coupling constant ¹³C/¹⁹F (Hz) Numbering (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/− 0.2 Hz)  6 176.56 — —  7  34.46 β: 2.96* 1 m (dd)J_(gem) = 17.3; J_(7β,8) = 10.2 α: 2.55 1 d  8  42.17 3.00* 1 m (dddd) 9  83.32 5.13 1 td J_(8,9) = J_(9,10β) = 6.4; J_(9,10α) = 1.3 10  37.50β: 2.63 1 dt J_(gem) = 15.2; J_(10β,11) = 6.4; α: 2.14 1 dd J_(10α,11) =3.6 11  78.95 5.35 1 dt J_(11,12) = 5.6 12  53.66 3.10 1 m (ddd)J_(8,12) = 5.0 13 146.19 6.99 1 dd J_(13,14) = 16.0; J_(12,13) = 8.1 14127.24 6.44 1 d 15 194.08 — — — 16  71.12 5.17 2 s 17 158.14 — — — 18111.16 (q) 7.22** 1 broad ³J_(C-18,F) = 3.8; J_(18,20) = 1.5; J_(18,22)= 2.5 19 130.24 (q) — — — ²J_(C-19,F) = 31.7 20 117.50 (q) 7.285 1 m (d)³J_(C-20,F) = 3.8; J_(20,21) = 7.8; J_(20,22) = 0.8; 21 130.63 7.495***1 m (dd) J_(21,22) = 8.2 22 118.75 7.20** 1 m (dd) 23 123.95 (q) — — —¹J_(C-23,F) = 272.5 23-F −61.10 — — — (s, 3) 24 164.94 — — — 25 128.16 —— — 26, 26′ 129.95 8.015 2 m J_(26,27) = 8.5; 27, 27′ 126.87 7.81 2 m 28144.93 — — — 29 138.77 — — — 30, 30′ 127.01 7.74 2 m (dd) J_(30,31) =7.4 31, 31′ 129.10 7.51*** 2 m (t) J_(31,32) = 7.4 32 128.46 7.43 1 m(tt) J_(30,32)~1.6 *, **, ***Overlapping ¹H NMR signals

2. 15-oxo-reduction (Stereoselective Reduction) Preparation of[1,1′-Biphenyl]-4-carboxylic acid,(3aR,4R,5R,6aS)-hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]-2-oxo-2H-cyclopenta[b]furan-5-ylester /compound of formula (III)/

279 ml of catecholborane is dissolved in 4.6 L of tetrahydrofuran (THF)and the 1M toluene solution of 549 ml ofR-(+)-2-methyl-CBS-oxazaborolidine is added to it. The mixture is cooledto −10° C. and while that temperature is maintained, the solution of 915g of Travoprost 1. intermediate (enone—compound of Formula (II)) in 6.9L of THF is added. When the reaction has completed, the mixture isdecomposed by stirring with 13 L of 1 M NaHSO₄ solution. Ethyl acetateis then added and the phases are separated. The organic phase is washedwith NaOH solution and then with hydrochloric acid solution. The organicphase is dried over sodium sulfate, filtered, evaporated andcrystallized first from hexane: acetone mixture, then from methanol forremoving the undesired isomer de(S)₉₂%->de(S)98%.

(de means: diastereomeric excess)

Yield: 701 g, 55% de(S): 98%

M.p.: 129.5-134.5° C.

IR spectrum of Travoprost 2. intermediate is shown on FIG. 3.

Travoprost 2. intermediate ¹H, ¹³C and ¹⁹F NMR data:

Coupling constant ¹³C/¹⁹F Number (Hz) Numbering (ppm) ¹H (ppm) of ¹HMultiplicity (+/− 0.2 Hz)  6 176.76 — — —  7  34.53 β: 2.93  1 ddJ_(gem) = 17.8; J_(7β,8) = 10.0 α: 2.46  1 dd J_(7α,8) = 0.9  8  42.14 2.85* 1 m (dddd)  9  83.28 5.09 1 td J_(8,9) = J_(9,10β) = 6.5;J_(9,10α) = 1.4 10  37.20 β: 2.55  1 dt J_(gem) = 15.2; J_(10β,11) =6.4; α: 2.05  1 m (dd) J_(10α,11) = 4.6 11  79.58 5.20 1 m (ddd/dt)J_(11,12)~5.5 12  53.49  2.83* 1 m (ddd) 13 129.87^($)  5.76** 1 m 14132.18  5.76** 1 m 15  68.83 4.34 1 m (broad) 15-OH 5.26 1 d J_(15, OH)= 4.9 16  72.18 a: 3.95  1 dd J_(gem) = 9.8; J_(15,16a) = 4.6; b: 3.90 1 dd J_(15,16b) = 6.7 17 158.88 — — — 18 111.08 (q)   7.195*** 1 m³J_(C-18,F) = 3.7 19 130.25 (q) — — — ²J_(C-19,F) = 31.5 20 117.04 (q)7.25 1 d ³J_(C-20,F) = 3.7; J_(20,21) = 7.7; J_(18,20) = 1.4; J_(20,22)= 1.0 21 130.63  7.47^(#) 1 m (t/dd) J_(21,22) = 8.2 22 118.80   7.20***1 m J_(18,22) = 2.5; 23 123.98 (q) — — — ¹J_(C-23,F) = 272.4 23-F −61.16— — — (s, 3) 24 165.02 — — — 25 128.33 — — — 26, 26′ 129.87^($) 7.99 2 dJ_(26,27) = 8.4 27, 27′ 126.80 7.77 2 d 28 144.81 — — — 29 138.77 — — —30, 30′ 126.97 7.72 2 d J_(30,31) = 7.4 31, 31′ 129.07  7.50^(#) 2 m (t)J_(31,32) = 7.4 32 128.42  7.43^(#) 1 m (tt) *, **, ***, ^(#), ^(##):Overlapping ¹H NMR signals. ^($): Overlapping ¹³C NMR signals.

3. Lactone reduction (Preparation of the Lactol)

Preparation of [1,1′-Biphenyl]-4-carboxylic acid, (3aR,4R,5R,6aS)-hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]-2-hydroxy-cyclopenta[b]furan-5-ylester /compound of formula (IV)/

A multi-neck flask is charged under nitrogen atmosphere with 701 g ofenol which is then dissolved in 6.8 L of room temperature THF. The clearsolution is cooled to −75° C. and in approximately 30 minutes thepre-cooled (−75° C.) 1 M hexane solution of 2921 ml diisobutylaluminumhydride (DIBAL-H) is added to it. The reaction mixture is stirred at−75° C. until the reaction is completed. After reaching the suitableconversion, the reaction mixture is poured onto the mixture of NaHSO₄solution and ethyl acetate. The phases are separated, the aqueous phaseis extracted with ethyl acetate, the united organic phase is washed withNaHCO₃ solution and with diluted hydrochloric acid solution, and thenevaporated while adding triethylamine (TEA) to it. 639.5 g oil isobtained.

Yield: 639.5 g, 91%

IR spectrum of Travoprost 3. intermediate is shown on FIG. 4.

Travoprost 3. intermediate ¹H, ¹³C and ¹⁹F NMR data:

Travoprost 3. intermediate, diastereomer A

Coupling constant ¹³C/¹⁹F (Hz) Numbering (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/−0.2 Hz)  6  98.78 5.53 1 td J_(6,OH) = 4.6; J_(6,7) =2.2 and 4.6  6-OH 6.02 1 d  7  39.31^($) a: 1.93* 1 m b: 1.89* 1 m  8 45.28 2.565** 1 m  9  79.43 4.565 1 td J_(8,9) = 6.2; J_(9,10) = 2.7and 6.2 10  37.21 β: 2.51 1 m J_(gem)~14.0 α: 1.74*** 1 m (ddd)J_(10α,11) = 6.9 11  79.72 5.08 1 m (q/dt) J_(10β,11) = J_(11,12) = 6.912  53.23 2.575** 1 m 13 130.60 5.75⁺ 1 dd J_(13,14) = 15.6; J_(12,13) =6.5 14 131.71 5.70⁺ 1 dd J_(14,15) = 4.5 15  68.79 4.32⁺⁺ 1 m (dddd)15-OH 5.23⁺⁺⁺ 1 m (d) J_(15,OH) = 5.0 16  72.23^($$) a: 3.91^(#) 1 m(dd) J_(gem) = 9.7; J_(15,16a) = 4.8; b: 3.87^(#) 1 m (dd) J_(15,16b) =6.7 17 158.88^($$) — — — 18 111.09 (q) 7.16^(##) 1 m ³J_(C-18,F) = 3.6;J_(18,20)~J_(18,22)~1.3 19 130.24^($$) — — — ²J_(C-19,F) = 31.7 (q) 20117.01^($$) 7.22^(###) 1 m ³J_(C-20,F) = 3.8; J_(20,21) = 7.8 (q) 21130.56 7.44^(&) 1 m (t/dd) J_(21,22) = 7.8 22 118.73 7.15^(##) 1 m 23123.97^($$) — — — ¹J_(C-23,F) = 272.4 (q) 23-F −61.19 — — — (s, 3) 24165.16 — — — 25 128.61 — — — 26, 26′ 129.75^($$) 7.985^(&&) 2 dJ_(26,27) = 8.4 27, 27′ 126.90^($$) 7.77 2 d 28 144.71^($$) — — — 29138.84^($$) — — — 30, 30′ 126.96^($$) 7.70^(&&&) 2 m (d) J_(30,31) = 7.531, 31′ 129.07^($$) 7.50

2 m (t/dd) J_(31,32) = 7.4 32 128.40^($$) 7.43^(&) 1 m (tt) *, **, ***,⁺, ⁺⁺, ⁺⁺⁺, ^(#), ^(##), ^(###), ^(&), ^(&&), ^(&&&),

Overlapping ¹H NMR signals. ^($)Overlapping ¹³C NMR signals with theDMSO signal. ^($$)Overlapping ¹³C NMR signals.

Travoprost 3. intermediate, diastereomer B

Coupling constant ¹³C/¹⁹F (Hz) Numbering (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/−0.2 Hz)  6  99.70 5.45 1 m (td/ddd) J_(6,7) = 0.9 and4.5  6-OH 6.25 1 d J_(6,OH) = 3.4  7  37.51 β: 1.99

1 m J_(7,8β) = 5.7 α: 1.73*** 1 m J_(gem)~11.8; J_(6,7α)= 1.9  8  44.642.41 1 m (q/ddd) J_(8,12) = 10.1  9  80.04 4.46 1 td J_(8,9) = J_(9,10β)= 7.3; J_(19,10α) = 5.2 10  39.45^($) β: 2.65 1 dt J_(gem) = 13.0;J_(10β,11) = 7.3 α: 1.90* 1 m 11  78.11 5.00 1 td J_(10α,11) = J_(11,12)= 9.8 12  52.34 3.10 1 td J_(12,13) = 7.1 13 130.74 14 131.85 15  68.6815-OH 5.21⁺⁺⁺ 1 m (d) J_(15,OH) = 5.1 16  72.25^($$) a: 3.88^(#) 1 mJ_(gem) = 9.7 b: 3.84^(#) 1 m (dd) J_(15,16b) = 6.6 17 158.86^($$) — — —19 130.22^($$) — — — ²J_(C-19,F) = 31.7 (q) 20 116.97^($$) 7.205^(###) 1m ³J_(C-20,F) = 3.8; J_(20,21) = 7.8 (q) 21 7.41^(&) 1 m (dd) J_(21,22)= 8.1 22 118.64 7.11^(##) 1 m (dd) 2.3; 0.8 23 123.95^($$) — — —¹J_(C-23,F) = 272.4 (q) 23-F −61.21 — — (s, 3^(%)) 24 165.28 — — — 25128.57 — — — 26, 26′ 129.76^($$) 7.995^(&&) 2 d J_(26,27) = 8.4 27, 27′126.85^($$) 7.73 2 d 28 144.68^($$) — — — 30, 30′ 126.94^($$) 7.68^(&&&)2 m (d) J_(30,31) = 7.5 31, 31′ 129.065^($$) *, ***, ⁺⁺⁺, ^(#), ^(##):^(###), ^(&), ^(&&), ^(&&&): Overlapping ¹H NMR signals. ^($)Overlapping¹³C NMR signals with the signal of DMSO.

Overlapping ¹H NMR signals with the signal of ethyl acetate.^($$)Overlapping ¹³C NMR signals. ^(%)The presence of the 3 fluoro atomsis shown by the ¹⁹F and ¹³C NMR spectra.

4. Removal of the Protecting Group (Preparation of the Triol) 4a.

Preparation of 2H-cyclopenta[b]furan-2,5-diol,hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]-,(3 aR,4R,5R,6aS)- /Compound of formula (V)/

639.5 g of PPB-triol is dissolved in 6.4 L of methanol and the solutionis heated to 40° C. 95 g of K₂CO₃ is added and the mixture is stirred at40° C. until the reaction is completed. After reaching the suitableconversion, the reaction mixture is cooled to 2° C. and phosphoric acidsolution is added in portions. The precipitated PPB-methyl estercrystals are filtered off and washed. The filtrate is concentrated,water and ethyl acetate are added and the phases are separated. Theaqueous phase is extracted with ethyl acetate, dried over Na₂SO₄ and thesolution is evaporated. The crude oil is crystallized from ethylacetate:hexane mixture. The precipitated crystals are filtered off,washed with hexane:ethyl acetate mixture and dried.

Yield: 367 g, 85%

Melting point: 85.4-86.6° C.

4b.

Recrystallyzation of 2H-cyclopenta[b]furan-2,5-diol,hexahydro-4-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]-,(3 aR,4R,5R,6aS)- /Compound of formula (V)—the triol/

The precipitated crystals are solved in 10 folds ethyl-acetate,thereafter 10 folds n-hexane is added and the solution is mixed at roomtemperature. To the crystal-suspension obtained 20 folds n-hexane isadded and mixed at room temperature. The precipitated crystals arefiltered, washed with a mixture of hexane:ethyl-acetate and dried. Withrepetition of the above process at any time the amount of the undesiredisomer may be lowered to any amount, also decreasing of the amount ofthe undesired isomer under the disregard limit (<0.05%) is possible.

Yield: 52-85% (depending of the number of recrystallizations)

IR spectrum of Travoprost 4. intermediate is shown on FIG. 5.

Travoprost 4. intermediate ¹H, ¹³C and ¹⁹F NMR data:

Travoprost 4. intermediate, diastereomer A ¹H, ¹³C and ¹⁹F NMR data:

Coupling constant ¹³C/¹⁹F (Hz) Numbering (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/−0.2 Hz)  6  98.73 5.42 1 td J_(6,7)~4.6 and 2.6  6-OH5.90 1 d J_(6,OH) = 4.6  7  39.04^($) 1.75 2 m  8  44.65 2.27** 1 m  9 78.29 4.345*** 1 td J_(8,9) = J_(9,10β) = 7.1; J_(9,10α) = 4.3 10 40.58 β: 2.24** 1 m J_(gem) = 14.0; J_(10α,11) = 9.1 α: 1.44 1 m (ddd)11  76.60 3.67 1 m (dddd) J_(10β,11) = 7.2; J_(11,12) = 9.2 11-OH 4.80 1d J_(6,OH) = 5.9 12  55.97 1.95⁺ 1 m (td) J_(8,12) = 9.2; J_(12,13) =7.4 13 132.44 5.69 1 dd J_(13,14) = 15.6 14 130.30 5.55 1 dd J_(14,15) =5.6 15  69.24 4.32*** 1 m 15-OH 5.16⁺⁺ 1 d J_(15,OH) = 4.9 16 72.48^($$) a: 3.97⁺⁺⁺ 1 m (dd) J_(gem) = 9.9; J_(15,16a) = 4.4; b:3.92^(#) 1 m (dd) J_(15,16b) = 7.0 17 158.99^($$) — — — 18 111.17 (q)7.22 1 m (dd) ³J_(C-18,F) = 3.7; J_(18,20) = 1.6; J_(18,22) = 3.6 19130.28 (q) — — — ²J_(C-19,F) = 31.7 20 117.04 (q) 7.27^(##) 1 m (dd)³J_(C-20,F) = 3.8; J_(20,21) = 8.0 21 130.70 7.51 1 m (t) J_(21,22) =8.0 22 118.93 7.25^(##) 1 m (dd) J_(20,22) = 1.0 23 124.03 (q) — — —¹J_(C-23,F) = 272.5 23-F −61.14 (s, — — — 3) *, **, ***, ⁺, ⁺⁺, ⁺⁺⁺,^(#), ^(##): Overlapping ¹H NMR signals. ^($)Overlapping ¹³C NMR signalswith the signal of DMSO. ^($$): Overlapping ¹³C NMR signal.

Travoprost 4. intermediate, diastereomer B H, ¹³C and ¹⁹F NMR data:

Coupling constant (Hz) Numbering ¹³C (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/−0.2 Hz)  6 99.55 5.36 1 m (t/ddd) J_(6,7β) = 5.1  6-OH6.10 1 d J_(6,OH) = 3.8  7 37.86 β: 1.92⁺ 1 m J_(7,8β) = 5.7 α: 1.61 1 mJ_(gem) = 12.9; J_(6,7α)~1.5  8 44.85 2.18** 1 m (dt/dddd) J_(7α,8)~1.5;J_(8,12) = 9.9  9 80.07 4.28*** 1 td J_(8,9) = J_(9,10β) = 7.8;J_(9,10α) = 5.7 10 42.88 β: 2.26** 1 m J_(gem) = 12.7; J_(10α,11) = 9.9α: 1.72* 1 m (ddd) 11 76.02 3.59 1 m (dddd) J_(10α,11) = 6.5; J_(11,12)= 9.9 11-OH 4.75 1 d J_(6,OH) = 5.9 12 55.03 2.52^(###) 1 m (td)J_(12,13)~7.3, 13 133.10 14 130.08 15 69.32 15-OH 5.15⁺⁺ 1 m (d)J_(15,OH) = 4.9 16 72.53^($$) a: 3.98^(#) 1 m (dd) J_(gem) = 9.9;J_(15,16a) = 4.4 b: 3.92^(#) 1 m (dd) J_(15,16b) = 6.9 17 159.01^($$) —— — *, ***, ⁺⁺⁺, ^(#), ^(##): Overlapping ¹H NMR signals.^(###)Overlapping ¹H NMR signals with the signal of DMSO.^($$)Overlapping ¹³C NMR signals.

5. Construction of the Upper Chain (Preparation of Travoprost Acid)

Preparation of 5-heptanoic acid,7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1-buten-1-yl]cyclopentyl]-,(5Z)- /Compound of formula (VI)/

Under nitrogen atmosphere 1509 g of 4-carboxybutyl-phosphonium bromide(KBFBr) is dissolved in 12.8 L of THF, the solution is cooled to 0° C.,and by maintaining that temperature, 1.12 kg of potassium tert-butylateis added to it in portions. After 15 minutes of stirring the reactionmixture is cooled to (−)10° C., then 367 g of triol dissolved in 2.24 Lof THF is added and the mixture is stirred at (−10)° C. When thereaction has completed, the reaction mixture is decomposed with waterand toluene is added. The aqueous phase is extracted withdichloromethane (DKM) and acidified with a solution of NaHSO₄. Ethylacetate is then added, the phases are separated and the aqueous phase isextracted with ethyl acetate. The united organic phase is washed with adiluted sodium chloride solution, dried over Na₂SO₄, the drying materialis filtered off, the filtrate is washed and the filtrate solution isevaporated. The residue is crystallized from acetone:diisopropyl ethermixture. The crystals are filtered off, washed with diisopropylether:acetone mixture. The mother liquor is evaporated.

Yield: 463 g, 103%

IR spectrum of Travoprost 5. intermediate is shown on FIG. 6.

Travoprost 5. intermediate ¹H, ¹³C and ¹⁹F NMR data:

Coupling constant Number (Hz) Numbering ¹³C/¹⁹F (ppm) ¹H (ppm) of ¹HMultiplicity (+/− 0.2 Hz)  1 174.37 — — —  1-COOH 11.95  1 broad (s)  2 33.09  2.13* 2 t J_(2,3) = 7.4  3  24.46  1.49** 2 m (tt) J_(3,4) = 7.4 4  26.06   1.96*** 2 m  5 128.56 5.23 1 dt J_(5,6) = 10.7; J_(4,5) =7.2  6 129.73 5.43 1 dt J_(6,7) = 7.4  7  24.78 b: 2.10*  1 m  a:1.96*** 1 m  8  48.78 1.32 1 m (dddd/tt) 11.1; 10.0; 5.0; 5.0  9  69.58  3.90⁺ 1 m  9-OH     4.36⁺⁺ 1 broad (s) 10  43.96 b: 2.20*  1 dddJ_(gem) = 14.1; J_(10b,11) = 8.4; a: 1.44** 1 ddd J_(9,10b) = 5.8;J_(10a,11) = 5.6; J_(9,10a) = 2.3; 11  75.64 3.69 1 m 11-OH 4.53 1 broad(s) 12  54.30  2.18* 1 m (td) 13 133.97 5.57 1 dd J_(13,14) = 15.5;J_(12,13) = 8.0 14 131.01 5.51 1 dd J_(14,15) = 5.7 15  69.51     4.32⁺⁺1 q (ddd) 5.6 15-OH  5.125 1 broad (s) 16  72.55 b: 3.96⁺   1 dd J_(gem)= 9.9; J_(15,16b) = 4.9 a: 3.93⁺   1 dd J_(15,16a) = 6.6 17 158.97 — — —18 111.13 (q)   7.20⁺ 1 m (t/dd) ³J_(C-18,F) = 3.7; J_(18,20) = 15;J_(18,22) = 2.5 19 130.29 (q) — — — ²J_(C-19,F) = 31.7 20 117.01 (q)      7.26⁺⁺⁺ 1 m (ddd) ³J_(C-20,F) = 3.8; J_(20,21) = 7.8; J_(20,22) =0.7 21 130.68 7.50 1 t (dd) J_(21,22) = 8.2 22 118.75       7.24⁺⁺⁺ 1 m(ddd) 23 124.01 (q) — — — ¹J_(C-23,F) = 272.4 23-F −61.19 — — — (s, 3)*, **, ***, ⁺, ⁺⁺, ⁺⁺⁺: Overlapping ¹H NMR signals.

6. Preparation of Travoprost /Compound of formula (I)/

463 g of Travoprost acid is dissolved in 2.3 L of1,3-dimethylimidazolidinone (DMI), and 420 g of K₂CO₃ and 300 ml ofisopropyl iodide are added. The reaction mixture is stirred at 45° C.After the completion of the reaction NaHSO₄ solution, water, hexane andethyl acetate are added. The mixture is shaken, then the phases areseparated and the lower, aqueous phase is extracted with hexane:ethylacetate mixture. The united organic phase is washed with water, driedover Na₂SO₄, the drying material is filtered off and the solution isevaporated. The product is purified by chromatography on silica gel,using diisopropyl ether, acetone, dichloromethane, isopropanol mixtureas eluent.

Yield: 338.7 g, 67%

IR spectrum of Travoprost is shown on FIG. 7.

Travoprost ¹H, ¹³C and ¹⁹F NMR data:

Coupling constant (Hz) Numbering ¹³C (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/− 0.2 Hz)  1 172.23 — — —  2  33.19  2.16* 2 t J_(2,3) =7.3  3  24.42  1.49** 2 tt J_(3,4) = 7.3  4  25.93   1.96*** 2 m (q)J_(4,5) = 7.3  5 128.36 5.23 1 dt J_(5,6) = 10.7  6 129.85 5.44 1 dtJ_(6,7) = 7.4  7  24.75 b: 2.09   1 m (dt)  a: 1.96*** 1 m  8  48.761.31 1 m (dddd/tt) 11.2; 10.0; 4.8; 4.8  9  69.54^($) 3.90 1 m (dddd)2.0; 5.3; 5.3, 5.3  9-OH 4.36 1 d J_(9,OH) = 4.9 b: 2.20*  1 m (ddd)J_(gem) = 14.1; J_(10b,11) = 8.7; 10  43.96 a: 1.44** 1 ddd J_(9,10b) =5.9; J_(10a,11) = 5.7; J_(9,10a) = 2.3; 11  75.63 3.69 1 m (dddd/tt)7.9; 7.9; 5.9; 5.9 11-OH 4.54 1 d J_(11,OH) = 5.8 12  54.30  2.175* 1 m13 134.01 5.57 1 dd J_(13,14) = 15.5; J_(12,13) = 8.0 14 131.03 5.51 1dd J_(14,15) = 6.0 15  69.54^($)  4.315 1 qui (tt) 5.5 15-OH 5.12 1 dJ_(15,OH) = 4.8 a: 3.94  1 m 16  72.55 b: 3.95   1 m 17 158.96 — — — 18111.07 (q) 7.20 1 m ³J_(C-18,F) = 3.7; J_(18,20) = ; J_(18,22) = 2.0 19130.28 (q) — — — ²J_(C-19,F) = 31.8 20 117.02 (q)   7.27⁺ 1 t³J_(C-20,F) = 3.9; J_(20,21) = 8.0; J_(20,22) = 0.7 21 130.67 7.51 1 tJ_(21,22) = 8.0; 22 118.77   7.24⁺ 1 dd 23 124.01 (q) — — — ¹J_(C-23,F)= 272.2 23-F −61.28 — — — (s, 3) 24  66.80 4.84 1 sep J_(24,25) = 6.325; 26  21.55 1.13 6 d ^($): Overlapping ¹³C NMR signals. *, **, ***, ⁺:Overlapping ¹H NMR signals.

1. A process for the preparation of travoprost of formula (I).

comprising that, the compound of formula (II).

is stereoselectively reduced, the resulting compound of formula (III)

is if desired crystallized, the lactone group of the compound of formula(III) is reduced, the p-phenyl-benzoyl protecting group of the thusobtained compound of formula (IV)

is removed, the resulting triol of formula (V)

is if desired after crystallization transformed by Wittig reaction intothe acid of formula (VI),

which is then esterified.
 2. The process as defined in claim 1,comprising that the selective reduction of the compound of formula (II)is carried out with a borane-type reducing agent.
 3. The process asdefined in claim 2, comprising that as borane-type reducing agentcatecholborane is applied.
 4. The process as defined in claim 2,comprising that the reduction of the compound of formula (II) is carriedout in the presence of a chiral catalyst.
 5. The process as defined inclaim 4, comprising that CBS-oxazaborolidine is used as catalyst.
 6. Theprocess as defined in claim 2, comprising that the reduction isperformed in hydrocarbon- or ether-type solvents.
 7. The process asdefined in claim 6, comprising that the reduction is performed intoluene, hexane, heptane, pentane, tetrahydrofuran,methyltetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane,tert-butyl methyl ether, diisopropyl ether, diethyl ether or in themixture of them.
 8. The process as defined in claim 7, comprising thatthe reduction is performed in a toluene-tetrahydrofuran mixture.
 9. Theprocess as defined in claim 2, comprising that the reduction is carriedout at a temperature between (−)10 and (−)90° C.
 10. The process asdefined in claim 9, comprising that the reduction is carried out at atemperature between (−)10 and (−)20° C.
 11. The process as defined inclaim 2, comprising that the resulting compound of formula (III) ispurified by crystallization.
 12. The crystallization as defined in claim11, comprising that the crystallization is carried out in hydrocarbon,chlorinated hydrocarbon, ether, ester, ketone or alcohol-type solventsor in the mixture of them.
 13. The crystallization as defined in claim12, comprising that the crystallization is carried out repeatedly, indifferent solvents or in the mixture of them.
 14. The crystallization asdefined in claim 13, comprising that the crystallization is carried outin hexane:acetone mixture and/or in methanol.
 15. The crystallization asdefined in claim 11, comprising that the crystallization is carried outat a temperature between (−20)-70° C. in such a way that the material isdissolved in alcohol at reflux temperature, crystallized by coolinggradually, and then filtered off, washed and dried.
 16. The process asdefined in claim 1, comprising that the reduction of the compound offormula (III) is carried out with diisobutylaluminum hydride.
 17. Theprocess as defined in claim 1, comprising that the p-phenylbenzoylprotecting group of the compound of formula (IV) is removed bymethanolysis, under basic conditions.
 18. The process as defined inclaim 17, comprising that the protecting group is removed in thepresence of potassium carbonate.
 19. The process as defined in claim 1,comprising that the intermediate of formula (V) is purified bycrystallization.
 20. The process as defined in claim 19, comprising thatthe crystallization is carried out in the mixture of polar and apolarsolvents.
 21. The process as defined in claim 20, comprising that thecrystallization is carried out in ethyl acetate-hexane mixture.
 22. Theprocess as defined in claim 20, comprising that the amount of theundesired isomer is decreased under the disregarding limit (0.05%) withadequate repetition of the crystallization process
 23. The process asdefined in claim 1, comprising that esterification of the compound offormula (VI) is carried out with isopropyl iodide.
 24. The process asdefined in claim 23, comprising that the esterification is carried outin cyclic tertiary-amide type solvents.
 25. The process as defined inclaim 24, comprising that as cyclic tertiary-amide type solventN-methylpyrrolidone or 1,3-dimethylimidazolidinone is applied.
 26. Theprocess as defined in claim 23, comprising that the esterification iscarried out within a temperature range of 20-90° C.
 27. The process asdefined in claim 26, comprising that the esterification is carried outwithin a temperature range of 40-50° C.
 28. The process as defined inclaim 1, comprising that the product of formula (I) is purified bychromatography.
 29. The process as defined in claim 28, comprising thatthe product is purified by gravimetric silica gel chromatography. 30.The process as defined in claim 29, comprising that the chromatographicpurification is performed using hydrocarbon, chlorinated hydrocarbon,ether, ester, alcohol, ketone and acid-type solvents or their mixtures,as eluents.
 31. The compound of formula (IV)


32. Use of the compound of formula (IV) as defined in claim 30, for thepreparation of travoprost of formula (I).
 33. The process for thepreparation of the compound of formula (IV), comprising that thecompound of formula (II)

is stereoselectively reduced, and the lactone group of the resultingcompound of formula (III)

is reduced.
 34. The crystalline compound of formula (III)

having the melting point of 129.5-134.5° C.
 35. Use of the crystallinecompound of formula (III) as defined in claim 33, for the preparation ofTravoprost of formula (I).
 36. The crystalline compound of formula (V).,

having the melting point of 85.4-86.6° C.
 37. The crystalline compoundof formula (V) as defined in claim 35, having an amount of the undesiredisomer less than 0.05%.
 38. Use of the crystalline compound of formula(V) as defined in claim 35, for the preparation of Travoprost of formula(I).